Entecavir, i.e., Compound 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-6H-purine-6-one as shown in Formula (1) below, is a new nucleoside type of anti-viral agent.

Entecavir is the third anti-HBV (Hepatitis B virus) drug which is marketed following Lamivudine and Adefovir Dipivoxil, and it has the highest anti-HBV activity among current anti-HBV drugs in the market. The anti-HBV effect of Entecavir is 100 times higher than Lamivudin, and is more than 30 times higher than Adefovir Dipivoxil. Moreover, its adverse effect is very low, its selection index is more than 8000, and it also has good therapeutic effect on Lamivudin-resistant HBV viruses. Thus, Entecavir provides theoretical possibility of healing Hepatitis B.
Up to now, the synthetic routes of preparing Entecavir mainly include the following routes.
Chinese patent ZL91110831.9 and International application WO98/09964 disclosed a method for preparation of Entecavir. Said method uses cyclopentadiene 8 as the starting material. Cyclopentadiene 8 is reacted with chloromethyl benzyl ether, followed by reacting with dipinene-borane complex (Ipc2BH) prepared from (+)-α-pinene, to afford chiral Intermediate 9. Then epoxidation of Intermediate 9 by t-BuO2H under catalysis of acetylacetone vanadium oxide [VO(acac)2] gives Intermediate 10. Reaction of Intermediate 10 with sodium hydride, tetrabutylammonium iodide and benzyl bromide affords Intermediate 11. Reaction of Intermediate 11 with lithium hydride and 6-benzyloxy-2-aminopurine 12 gives Intermediate 13. (mono-p-methoxy-triphenyl)-methyl chloride (MMTCl) is used to protect the amino of Intermediate 13 to afford Intermediate 14, which is subsequently oxidized with Dess-Martin reagent so as to oxidize hydroxy group to ketone group, thereby yielding Intermediate 15. Intermediate 15 is treated with Nysted reagent and titanium tetrachloride to perform methylenation, to give Intermediate 16. Then Intermediate 16 is reacted with hydrochloric acid to cleave the MMT group on the amino group and the benzyl group on the purine ring, to obtain Intermediate 17. Finally Intermediate 17 is treated with boron trichloride to cleave benzyl groups on the hydroxyl groups of the cycloalkyl. The method is shown as the following scheme.

There are some problems in above preparation method. The starting materials include chiral boron reagent which is very expensive, removing benzyl in the last step utilizes hypertoxic boron trichloride, the synthetic steps of the Intermediates are difficult and need harsh conditions and high-quality equipments, and some reagents used in above method are expensive.
In addition, a patent application (Publication No. WO2004/052310A2) of Bristol Meyer Squibb Company disclosed a synthetic method using compound 2′ as starting material, which is shown in the following scheme.

However, when the applicant used above method of WO2004/052310A2 to synthesize Entecavir, Mitsunobu reaction of 2-aminopurine compound 23 (in which the amino group was not protected) with Intermediate 4 as described in said method was found to have lower and instable yield. Moreover, the coupling reaction product 24 of said Mitsunobu reaction has similar polarity to triphenyl phosphine oxide generated from the reagent triphenylphosphine, thus it is difficult to isolate and purify the reaction product. Furthermore, the Intermediate 25 obtained by removing hydroxy-protecting group from the reaction product 24 has high water-solubility, thus it is difficult to obtain the Intermediate 25 by simple extraction and isolation, and its yield is low. Therefore, the method of WO2004/052310A2 was considered unsuitable to large-scale industrial production.
Furthermore, although above method also mentioned a photochemistry method in which compound 2′ used as starting material is treated with iodophenyl acetate and iodine can be utilized to generate an iodide, and said iodide is subjected to elimination reaction followed by alcoholysis to prepare Intermediate 4, the patent application failed to provide specific experimental examples and experimental data to prove feasibility of said method.
When the inventor of the present invention used the reported conditions (PhI(OAc)2/I2, hv (Tetrahedron Letters, 1987, 28, 3397-3400)) according to above method of WO 2004/052310A2 to prepare Intermediate 4, he found the yield of said method was low, thus it is difficult to apply said method to industrial production.
Another method was disclosed in Chinese Chemical Letters, 2006, 17(7) 907-910 and Chinese patent application publication CN 1861602A, which is shown in the following scheme.

However, above method has long synthetic route and complicated operations, thus it is difficult to apply said method to industrial production.
Therefore, there is still a need for development of a new preparation method now, which can overcome above-mentioned problems and is convenient to use in industrial production.